Crystalline forms of (R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

ABSTRACT

This invention relates to crystalline forms of (R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile, a modulator of the androgen receptor, and methods for the use in treatment.

This application is a continuation of U.S. application Ser. No.15/111,068 filed on Jul. 12, 2016, which is a 371 National Stage Entryof International PCT/I B2015/050440, filed on Jan. 20, 2015, whichclaims priority from U.S. Provisional Application 61/929,814 filed onJan. 21, 2014, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to crystalline forms of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile,a modulator of the androgen receptor, and methods for the use intreatment.

BACKGROUND OF THE INVENTION

Steroidal nuclear receptor (NR) ligands are known to play importantroles in the health of both men and women. Testosterone (T) anddihydrotestosterone (DHT) are endogenous steroidal ligands for theandrogen receptor (AR) that appear to play a role in every tissue typefound in the mammalian body. During the development of the fetus,androgens play a role in sexual differentiation and development of malesexual organs. Further sexual development is mediated by androgensduring puberty. Androgens play diverse roles in the adult, includingstimulation and maintenance of male sexual accessory organs andmaintenance of the musculoskeletal system. Cognitive function,sexuality, aggression, and mood are some of the behavioral aspectsmediated by androgens. Androgens have a physiologic effect on the skin,bone, and skeletal muscle, as well as blood, lipids, and blood cells(Chang, C. and Whipple, G. Androgens and Androgen Receptors. KluwerAcademic Publishers: Boston, Mass., 2002)

Many clinical studies with testosterone have demonstrated significantgains in muscle mass and function along with decreases in visceral fat.See, for example, Bhasin (2003) S. J. Gerontol. A Biol. Sci. Med. Sci.58:1002-8, and Ferrando, A. A. et al. (2002) Am. J. Phys. Endo. Met.282: E601-E607. Androgen replacement therapy (ART) in men improves bodycomposition parameters such as muscle mass, strength, and bone mineraldensity (see, for example, Asthana, S. et al. (2004) J. Ger., Series A:Biol. Sci. Med. Sci. 59: 461-465). There is also evidence of improvementin less tangible parameters such as libido and mood. Andrologists andother specialists are increasingly using androgens for the treatment ofthe symptoms of androgen deficiency. ART, using T and its congeners, isavailable in transdermal, injectable, and oral dosage forms. All currenttreatment options have contraindications (e.g., prostate cancer) andside-effects, such as increased hematocrit, liver toxicity, and sleepapnoea. Side-effects from androgen therapy in women include: acne,hirsutism, and lowering of high-density lipoprotein (HDL) cholesterollevels, a notable side-effect also seen in men.

Agents that could selectively afford the benefits of androgens andgreatly reduce the side-effect profile would be of great therapeuticvalue. Interestingly, certain NR ligands are known to exert their actionin a tissue selective manner (see, for example, Smith et al. (2004)Endoc. Rev. 2545-71). This selectivity stems from the particular abilityof these ligands to function as agonists in some tissues, while havingno effect or even an antagonist effect in other tissues. The term“selective receptor modulator” (SRM) has been given to these molecules.A synthetic compound that binds to an intracellular receptor and mimicsthe effects of the native hormone is referred to as an agonist. Acompound that inhibits the effect of the native hormone is called anantagonist. The term “modulators” refers to compounds that have aspectrum of activities ranging from full agonism to partial agonism tofull antagonism.

SARMs (selective androgen receptor modulators) represent an emergingclass of small molecule pharmacotherapeutics that have the potential toafford the important benefits of androgen therapy without the undesiredside-effects. Many SARMs with demonstrated tissue-selective effects arecurrently in the early stages of development See, for example, Mohler,M. L. et al. (2009) J. Med. Chem. 52(12): 3597-617. One notable SARMmolecule, Ostarine™, has recently completed phase I and II clinicalstudies. See, for example, Zilbermint, M. F. and Dobs, A. S. (2009)Future Oncology 5(8):1211-20. Ostarine™ appears to increase total leanbody mass and enhance functional performance. Because of theirhighly-selective anabolic properties and demonstrated androgenic-sparingactivities, SARMs should be useful for the prevention and/or treatmentof many diseases in both men and women, including, but not limited tosarcopenia, cachexias (including those associated with cancer, heartfailure, chronic obstructive pulmonary disease (COPD), and end stagerenal disease (ESRD), urinary incontinence, osteoporosis, frailty, dryeye and other conditions associated with aging or androgen deficiency.See, for example, Ho et al. (2004) Curr Opin Obstet Gynecol. 16:405-9;Albaaj et al. (2006) Postgrad Med J 82:693-6; Caminti et al. (2009) J AmColl Cardiol. 54(10):919-27; lellamo et al. (2010) J Am Coll Cardiol.56(16):1310-6; Svartberg (2010) Curr Opin Endocrinol Diabetes Obes.17(3):257-61, and Mammadov et al. (2011) Int Urol Nephrol 43:1003-8.SARMS also show promise for use in promoting muscle regeneration andrepair (see, for example, Serra et al. (Epub 2012 Apr. 12)doi:10.1093/Gerona/gls083), in the areas of hormonal male contraceptionand benign prostatic hyperplasia (BPH), and in wound healing (see, forexample, Demling (2009) ePlasty 9:e9).

Preclinical studies and emerging clinical data demonstrate thetherapeutic potential of SARMs to address the unmet medical needs ofmany patients. The demonstrated advantages of this class of compounds incomparison with steroidal androgens (e.g., tissue-selective activity,oral administration, AR selectivity, and lack of androgenic effect)position SARMs for a bright future of therapeutic applications.

Although amorphous forms of SARMs may be developed for some uses,compounds having high crystallinity are generally preferred forpharmaceutical use due to their improved solubility and stability.Accordingly, there remains a need in the art for crystalline form ofSARMs for therapeutic use.

BRIEF SUMMARY OF INVENTION

The present invention relates to crystalline forms of non-steroidalcompounds that are modulators of androgen receptor, and also to the useof these compounds in therapy.

The present invention provides a crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.In a preferred embodiment the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis anhydrous.

According to one aspect of the invention, the crystalline form ofanhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis Form 1.

In a particular embodiment, Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an X-ray powder diffraction (XRPD) pattern that hasthe representative peaks:

Position [° 2 Theta] d-spacing [Å]  9.2 ± 0.1 9.6 11.4 ± 0.1 7.8 11.9 ±0.1 7.4 13.8 ± 0.1 6.4 15.4 ± 0.1 5.7 17.8 ± 0.1 5.0 18.0 ± 0.1 4.9 18.5± 0.1 4.8 18.7 ± 0.1 4.7 23.2 ± 0.1 3.8

In another embodiment, Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an XRPD pattern substantially in accordance withFIG. 1.

In an additional embodiment, Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at −52.7±0.2,−56.0±0.2 and −57.1±0.2 ppm, wherein the ¹⁹F SSNMR spectrum is obtainedon a spectrometer operating at a frequency of 470.40 MHz for ¹⁹Fobservation using a cross-polarization pulse sequence with a Bruker 4-mmtriple resonance magic-angle spinning probe at a rotor frequency of 12.5kHz.

In one embodiment, Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum substantially in accordancewith FIG. 4.

In an additional embodiment, Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at 140.1±0.2,136.9±0.2, 134.9±0.2, 130.4±0.2, 128.5±0.2, 126.6±0.2, 126.0±0.2,125.7±0.2, 124.8±0.2, 121.9±0.2, 120.9±0.2, 119.7±0.2, 118.6±0.2,115.5±0.2, 115.1±0.2, 103.6±0.2, 100.3±0.2, 98.9±0.2, 58.1±0.2,55.7±0.2, 54.7±0.2, 51.1±0.2, 50.4±0.2, 44.7±0.2, 43.6±0.2, 40.7±0.2,23.5±0.2 and 20.7±0.2 ppm, wherein the ¹³C SSNMR spectrum is obtained ona spectrometer operating at a frequency of 125.73 MHz for ¹³Cobservation using a cross-polarization pulse sequence with a Bruker 4-mmtriple resonance magic-angle spinning probe at a rotor frequency of 8kHz.

In certain embodiments, Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR spectrum substantially in accordancewith FIG. 3.

According to another aspect of the invention, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis Form 2.

In one embodiment, Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an X-ray powder diffraction (XRPD) pattern that hasthe representative peaks:

Position [° 2 Theta] d-spacing [Å]  7.4 ± 0.1 11.9 12.7 ± 0.1 7.0 17.5 ±0.1 5.1 19.5 ± 0.1 4.6 21.9 ± 0.1 4.1 22.5 ± 0.1 3.9 23.9 ± 0.1 3.7 26.5± 0.1 3.4

In another embodiment, Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an XRPD pattern substantially in accordance withFIG. 2.

In an additional embodiment, Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum comprising isotropic chemicalshifts at −55.5±0.2 and −56.3±0.2 ppm, wherein the ¹⁹F SSNMR spectrum isobtained on a spectrometer operating at a frequency of 470.40 MHz for¹⁹F observation using a cross-polarization pulse sequence with a Bruker4-mm triple resonance magic-angle spinning probe at a rotor frequency of12.5 kHz.

According to one embodiment, Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum substantially in accordancewith FIG. 6.

According to another embodiment, Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at 138.4±0.2,127.4±0.2, 125.5±0.2, 124.3±0.2, 123.3±0.2 116.5±0.2, 114.1±0.2,104.7±0.2, 97.4±0.2, 61.8±0.2, 60.9±0.2, 59.2±0.2, 48.2±0.2, 47.6±0.2,46.3±0.2, 44.4±0.2, 42.3±0.2, and 26.1±0.2 ppm, wherein the ¹³C SSNMRspectrum is obtained on a spectrometer operating at a frequency of125.73 MHz for ¹³C observation using a cross-polarization pulse sequencewith a Bruker 4-mm triple resonance magic-angle spinning probe at arotor frequency of 8 kHz.

In an additional embodiment, Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR spectrum substantially in accordancewith FIG. 5.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a crystalline form of the present invention andone or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides a crystalline form ofthe present invention for use as an active therapeutic substance.

Another aspect of the present invention provides a crystalline form ofthe present invention for use in the acceleration of wound healing andburn healing and the treatment of hypogonadism, sarcopenia,osteoporosis, muscle wasting, wasting diseases, cachexia (includingcachexias associated with cancer, chronic obstructive pulmonary disease(COPD), end stage renal disease (ESRD), heart failure, HIV illness, HIVtreatment, and diabetes mellitus type 1 and type 2), frailty, dry eye,prostatic hyperplasia, prostate cancer, breast cancer, menopausal andandropausal vasomotor conditions, sexual dysfunction, erectiledysfunction, depression, uterine fibroid disease, endometriosis, urinaryincontinence (including urinary incontinence associated with muscleand/or tissue wasting of the pelvic floor), acne, hirsutism, malecontraception, impotence, and in the use as male and female hormonereplacement therapy, as a stimulant of hematopoiesis, and as an anabolicagent.

Another aspect of the present invention provides the use of acrystalline form of the present invention in the manufacture of amedicament for use in the acceleration of wound healing and thetreatment of hypogonadism, sarcopenia, osteoporosis, muscle wasting,wasting diseases, muscle wasting and cachexia (including muscle wastingand cachexias associated with cancer, chronic obstructive pulmonarydisease (COPD), end stage renal disease (ESRD), heart failure, HIVillness, HIV treatment, and diabetes mellitus type 1 and type 2),frailty, dry eye, prostatic hyperplasia, prostate cancer, breast cancer,menopausal and andropausal vasomotor conditions, urinary incontinence(including urinary incontinence associated with muscle and/or tissuewasting of the pelvic floor), sexual dysfunction, erectile dysfunction,depression, uterine fibroid disease, endometriosis, acne, hirsutism,male contraception, impotence, and in the use as male and female hormonereplacement therapy, as a stimulant of hematopoiesis, and as an anabolicagent.

Another aspect of the present invention provides a method for thetreatment of hypogonadism, sarcopenia, osteoporosis, muscle wasting,wasting diseases, cachexia and muscle wasting (including muscle wastingand cachexias associated with cancer, chronic obstructive pulmonarydisease (COPD), end stage renal disease (ESRD), heart failure, HIVillness, HIV treatment, and diabetes mellitus type 1 and type 2),frailty, prostatic hyperplasia, prostate cancer, breast cancer,menopausal and andropausal vasomotor conditions, chronic obstructivepulmonary disease (COPD), urinary incontinence (including urinaryincontinence associated with muscle and/or tissue wasting of the pelvicfloor), sexual dysfunction, erectile dysfunction, depression, uterinefibroid disease, endometriosis, acne, hirsutism, male contraception,impotence, and a method of male and female hormone replacement therapy,stimulation of hematopoiesis, and anabolism, wherein the methodcomprises administration of a crystalline form of the present invention.

In another aspect, the present invention provides a method for thetreatment of a muscle injury, and for accelerating muscle repaircomprising the administration of a crystalline form of the presentinvention. Also provided is the use of a crystalline form of the presentinvention in the treatment of a muscle injury, or in the acceleration ofmuscle repair. Additionally included is the use of a crystalline form ofthe present invention in the manufacture of a medicament for thetreatment of muscle injury or the acceleration of muscle repair.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the XRPD of crystalline form 1 of anhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.

FIG. 2 depicts the XRPD of crystalline form 2 of anhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.

FIG. 3 depicts the ¹³C solid state NMR (SSNMR) spectrum of crystallineform 1 of anhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.The solid state NMR spectrum was obtained on a spectrometer operating ata frequency of 125.73 MHz for ¹³C observation and a spinning speed of 8kHz, according to the procedures described herein. The 119.7 ppm carbonsite is split by the ¹J_(C-F) coupling, and the carbon sites at 55.7,43.6, and 23.5 ppm are likely the result of site disorder in the crystalstructure.

FIG. 4 depicts the isotropic region of the ¹⁹F solid state NMR (SSNMR)spectrum of the compound of crystalline form 1 of anhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.The solid state NMR spectrum was obtained on a spectrometer operating ata frequency of 470.40 MHz for ¹⁹F observation and a spinning speed of12.5 kHz, according to the procedures described herein. The ¹⁹Fresonance at 52.7 ppm is likely the result of site disorder in thecrystal structure.

FIG. 5 depicts the ¹³C solid state NMR (SSNMR) spectrum of the compoundof crystalline form 2 of anhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.The solid state NMR spectrum was obtained on a spectrometer operating ata frequency of 125.73 MHz for ¹³C observation and a spinning speed of 8kHz, according to the procedures described herein. The 116.5 ppm peakarises from a carbon site, split by the ¹J_(C-F) coupling.

FIG. 6 depicts the isotropic region of the ¹⁹F solid state NMR (SSNMR)spectrum of crystalline form 2 of anhydrous(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.The solid state NMR spectrum was obtained on a spectrometer operating ata frequency of 470.40 MHz for ¹⁹F observation and a spinning speed of12.5 kHz, according to the procedures described herein

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile:

In a particular embodiment, wherein the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis anhydrous. In a specific embodiment, the anhydrous crystalline formhas a water content of less than 1.5, preferably less than 1.0, morepreferably less than 0.5 percent by weight.

According to one aspect of the invention, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis Form 1.

In a particular embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an X-ray powder diffraction (XRPD) pattern that hasthe representative peaks:

Position [° 2 Theta] d-spacing [Å]  9.2 ± 0.1 9.6 11.4 ± 0.1 7.8 11.9 ±0.1 7.4 13.8 ± 0.1 6.4 15.4 ± 0.1 5.7 17.8 ± 0.1 5.0 18.0 ± 0.1 4.9 18.5± 0.1 4.8 18.7 ± 0.1 4.7 23.2 ± 0.1 3.8

In another embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an XRPD pattern substantially in accordance withFIG. 1.

In one embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at −56.0±0.5and −57.1±0.5 ppm, wherein the ¹⁹F SSNMR spectrum is obtained on aspectrometer operating at a frequency of 470.40 MHz for ¹⁹F observationusing a cross-polarization pulse sequence with a Bruker 4-mm tripleresonance magic-angle spinning probe at a rotor frequency of 12.5 kHz.

In an additional embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at −52.7±0.2,−56.0±0.2 and −57.1±0.2 ppm, wherein the ¹⁹F SSNMR spectrum is obtainedon a spectrometer operating at a frequency of 470.40 MHz for ¹⁹Fobservation using a cross-polarization pulse sequence with a Bruker 4-mmtriple resonance magic-angle spinning probe at a rotor frequency of 12.5kHz.

In one embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum substantially in accordancewith FIG. 4.

In one embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at 140.1±0.2,136.9±0.2, 134.9±0.2, 130.4±0.2, 128.5±0.2, 126.6±0.2, 124.8±0.2,119.7±0.2, 118.6±0.2, 115.5±0.2, 115.1±0.2, 103.6±0.2, 100.3±0.2,98.9±0.2, 58.1±0.2, 54.7±0.2, 51.1±0.2, 50.4±0.2, 44.7±0.2, 40.7±0.2,and 20.7±0.2 ppm, wherein the ¹³C SSNMR spectrum is obtained on aspectrometer operating at a frequency of 125.73 MHz for ¹³C observationusing a cross-polarization pulse sequence with a Bruker 4-mm tripleresonance magic-angle spinning probe at a rotor frequency of 8 kHz.

In an additional embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at 140.1±0.2,136.9±0.2, 134.9±0.2, 130.4±0.2, 128.5±0.2, 126.6±0.2, 126.0±0.2,125.7±0.2, 124.8±0.2, 121.9±0.2, 120.9±0.2, 119.7±0.2, 118.6±0.2,115.5±0.2, 115.1±0.2, 103.6±0.2, 100.3±0.2, 98.9±0.2, 58.1±0.2,55.7±0.2, 54.7±0.2, 51.1±0.2, 50.4±0.2, 44.7±0.2, 43.6±0.2, 40.7±0.2,23.5±0.2 and 20.7±0.2 ppm, wherein the ¹³C SSNMR spectrum is obtained ona spectrometer operating at a frequency of 125.73 MHz for ¹³Cobservation using a cross-polarization pulse sequence with a Bruker 4-mmtriple resonance magic-angle spinning probe at a rotor frequency of 8kHz.

In a certain embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR spectrum substantially in accordancewith FIG. 3.

According to another aspect of the invention, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis Form 2.

In one embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an X-ray powder diffraction (XRPD) pattern that hasthe representative peaks:

Position [° 2 Theta] d-spacing [Å]  7.4 ± 0.1 11.9 12.7 ± 0.1 7.0 17.5 ±0.1 5.1 19.5 ± 0.1 4.6 21.9 ± 0.1 4.1 22.5 ± 0.1 3.9 23.9 ± 0.1 3.7 26.5± 0.1 3.4

In another embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an XRPD pattern substantially in accordance withFIG. 2.

In an additional embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum comprising isotropic chemicalshifts at −55.5±0.2 and −56.3±0.2 ppm, wherein the ¹⁹F SSNMR spectrum isobtained on a spectrometer operating at a frequency of 470.40 MHz for¹⁹F observation using a cross-polarization pulse sequence with a Bruker4-mm triple resonance magic-angle spinning probe at a rotor frequency of12.5 kHz.

In another embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum comprising isotropic chemicalshifts at −55.5±0.5 and −56.3±0.5 ppm, wherein the ¹⁹F SSNMR spectrum isobtained on a spectrometer operating at a frequency of 470.40 MHz for¹⁹F observation using a cross-polarization pulse sequence with a Bruker4-mm triple resonance magic-angle spinning probe at a rotor frequency of12.5 kHz.

According to one embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹⁹F SSNMR spectrum substantially in accordancewith FIG. 6.

According to another embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR (solid state nuclear magneticresonance) spectrum comprising isotropic chemical shifts at 138.4±0.2,127.4±0.2, 125.5±0.2, 124.3±0.2, 123.3±0.2 116.5±0.2, 114.1±0.2,104.7±0.2, 97.4±0.2, 61.8±0.2, 60.9±0.2, 59.2±0.2, 48.2±0.2, 47.6±0.2,46.3±0.2, 44.4±0.2, 42.3±0.2, and 26.1±0.2 ppm, wherein the ¹³C SSNMRspectrum is obtained on a spectrometer operating at a frequency of125.73 MHz for ¹³C observation using a cross-polarization pulse sequencewith a Bruker 4-mm triple resonance magic-angle spinning probe at arotor frequency of 8 kHz.

In an additional embodiment, the crystalline form of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrileis characterized by an ¹³C SSNMR spectrum substantially in accordancewith FIG. 5.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a crystalline form of the present invention andone or more pharmaceutically acceptable excipients. In a preferredembodiment, the crystalline form in Form 1.

It is well known and understood to those skilled in the art that theapparatus employed, humidity, temperature, orientation of the powdercrystals, and other parameters involved in obtaining an X-ray powderdiffraction (XRPD) pattern may cause some variability in the appearance,intensities, and positions of the lines in the diffraction pattern. AnX-ray powder diffraction pattern that is “substantially in accordance”with that of FIG. 1 or 2 provided herein is an XRPD pattern that wouldbe considered by one skilled in the art to represent a compoundpossessing the same crystal form as the compound that provided the XRPDpattern of FIG. 1 or 2. That is, the XRPD pattern may be identical tothat of FIG. 1 or 2, or more likely it may be somewhat different. Suchan XRPD pattern may not necessarily show each of the lines of any one ofthe diffraction patterns presented herein, and/or may show a slightchange in appearance, intensity, or a shift in position of said linesresulting from differences in the conditions involved in obtaining thedata. A person skilled in the art is capable of determining if a sampleof a crystalline compound has the same form as, or a different formfrom, a form disclosed herein by comparison of their XRPD patterns. Forexample, one skilled in the art can overlay an XRPD pattern of a sampleof(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile,with FIG. 1 or 2 and, using expertise and knowledge in the art, readilydetermine whether the XRPD pattern of the sample is substantially inaccordance with the XRPD pattern shown in the figure. If the XRPDpattern is substantially in accordance with FIG. 1 (Form 1) or 2 (Form2), the sample form can be readily and accurately identified as havingthe same form as Form 1 or Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile.

Further, it is also well known and understood to those skilled in theart that the apparatus employed, humidity, temperature, orientation ofthe powder crystals, and other parameters involved in obtaining an SSNMRspectrum may cause some variability in the appearance, intensities, andpositions of the peaks in the spectrum. A SSNMR spectrum that is“substantially in accordance” with that of FIG. 3, 4, 5, or 6 providedherein is an SSNMR spectrum that would be considered by one skilled inthe art to represent a compound possessing the same crystal form as thecompound that provided the SSNMR spectrum of FIG. 3, 4, 5, or 6. Thatis, the SSNMR spectrum may be identical to that of FIG. 3, 4, 5, or 6,or more likely it may be somewhat different.

Such a SSNMR spectrum may not necessarily show each of the chemicalshifts of any one of the spectra presented herein, and/or may show aslight change in appearance, intensity, or a shift in position of saidchemical shift resulting from differences in the conditions involved inobtaining the data. A person skilled in the art is capable ofdetermining if a sample of a crystalline compound has the same form as,or a different form from, a form disclosed herein by comparison of theirSSNMR spectra. For example, one skilled in the art can overlay an SSNMRspectrum of a sample of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrilewith FIG. 3, 4, 5, or 6 and, using expertise and knowledge in the art,readily determine whether the SSNMR spectrum of the sample issubstantially in accordance with the SSNMR spectrum of CompoundB—anhydrous crystalline form. If the SSNMR spectrum is substantially inaccordance with 3(Form 1), 4(Form 1), 5(Form 2), or 6(Form 2), thesample form can be readily and accurately identified as having the sameform as that having a substantially similar spectrum as shown in therespective figure.

The crystalline forms of the present invention are believed to modulatethe function of one or more nuclear hormone receptor(s). Particularly,the crystalline forms of the present invention modulate the androgenreceptor (“AR”). The present invention includes crystalline forms thatare selective agonists, partial agonists, antagonists, or partialantagonists of the AR. Crystalline forms of the present invention areuseful in the treatment of AR-associated diseases and conditions, forexample, a disease or condition that is prevented, alleviated, or curedthrough the modulation of the function or activity of AR. Suchmodulation may be isolated within certain tissues or widespreadthroughout the body of the subject being treated.

As used herein, the term “treatment” refers to alleviating the specifiedcondition, eliminating or reducing the symptoms of the condition,slowing or eliminating the progression of the condition.

The crystalline forms of the present invention may also be useful inpreventing or delaying the initial occurrence of the condition in asubject, or reoccurrence of the condition in a previously afflictedsubject.

One embodiment of the present invention provides crystalline forms ofthe present invention for use in medical therapy. Particularly, thepresent invention provides for the treatment of disorders mediated byandrogenic activity. More particularly, the present invention providestreatment of disorders responsive to tissue-selective anabolic and orandrogenic activity. A further embodiment of the invention provides amethod of treatment of a mammal suffering from a disorder mediated byandrogenic activity, which includes administering to said subject aneffective amount of a crystalline form of the present invention.

The crystalline forms of the present invention may find use for thetreatment of a variety of disorders including, but not limited to,osteoporosis and/or the prevention of reduced bone mass, density, orgrowth, osteoarthritis, acceleration of bone fracture repair andhealing, acceleration of healing in joint replacement, periodontaldisease, acceleration of tooth repair or growth, Paget's disease,osteochondrodysplasias, muscle wasting, the maintenance and enhancementof muscle strength and function, frailty or age-related functionaldecline (ARFD), dry eye, sarcopenia, end-stage renal disease (ESRD),chronic fatigue syndrome, chronic myalgia, acute fatigue syndrome,sepsis, acceleration of wound healing, maintenance of sensory function,chronic liver disease, AIDS, weightlessness, burn and trauma recovery,thrombocytopenia, short bowel syndrome, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease and ulcerative colitis,obesity, eating disorders including anorexia associated with cachexia oraging, hypercortisolism and Cushing's syndrome, cardiovascular diseaseor cardiac dysfunction, congestive heart failure, high blood pressure,malignant tumor cells containing the androgen receptor including breast,brain, skin, ovary, bladder, lymphatic, liver, kidney, uterine,pancreas, endometrium, lung, colon, and prostate, prostatic hyperplasia,hirsutism, acne, seborrhea, androgenic alopecia, anemia, hyperpilosity,adenomas and neoplasis of the prostate, hyperinsulinemia, insulinresistance, diabetes, syndrome X, dyslipidemia, menopausal vasomotorconditions, urinary incontinence, atherosclerosis, libido enhancement,sexual dysfunction, depression, nervousness, irritability, stress,reduced mental energy and low self-esteem, improvement of cognitivefunction, endometriosis, polycystic ovary syndrome, counteractingpreeclampsia, premenstrual syndrome, contraception, uterine fibroiddisease, aortic smooth muscle cell proliferation, male hormonereplacement, or ADAM.

A further embodiment of the invention provides a method of treatment ofa mammal requiring the treatment of a variety of disorders including,but not limited to, osteoporosis and/or the prevention of reduced bonemass, density, or growth, osteoarthritis, acceleration of bone fracturerepair and healing, acceleration of healing in joint replacement,periodontal disease, acceleration of tooth repair or growth, Paget'sdisease, osteochondrodysplasias, muscle wasting, the maintenance andenhancement of muscle strength and function, frailty or age-relatedfunctional decline (ARFD), dry eye, sarcopenia, end-stage renal disease(ESRD), chronic fatigue syndrome, chronic myalgia, acute fatiguesyndrome, acceleration of wound healing, maintenance of sensoryfunction, chronic liver disease, AIDS, weightlessness, burn and traumarecovery, thrombocytopenia, short bowel syndrome, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease and ulcerativecolitis, obesity, eating disorders including anorexia associated withcachexia or aging, hypercortisolism and Cushing's syndrome,cardiovascular disease or cardiac dysfunction, congestive heart failure,high blood pressure, malignant tumor cells containing the androgenreceptor including breast, brain, skin, ovary, bladder, lymphatic,liver, kidney, uterine, pancreas, endometrium, lung, colon, andprostate, prostatic hyperplasia, hirsutism, acne, seborrhea, androgenicalopecia, anemia, hyperpilosity, adenomas and neoplasis of the prostate,hyperinsulinemia, insulin resistance, diabetes, syndrome X,dyslipidemia, menopausal vasomotor conditions, urinary incontinence(including urinary incontinence associated with muscle and/or tissuewasting of the pelvic floor), atherosclerosis, libido enhancement,sexual dysfunction, depression, nervousness, irritability, stress,reduced mental energy and low self-esteem, improvement of cognitivefunction, endometriosis, polycystic ovary syndrome, counteractingpreeclampsia, premenstrual syndrome, contraception, uterine fibroiddisease, aortic smooth muscle cell proliferation, male hormonereplacement, or ADAM. Preferably the crystalline forms of the presentinvention are used as male and female hormone replacement therapy or forthe treatment or prevention of hypogonadism, osteoporosis, musclewasting, wasting diseases, cancer cachexia, frailty, prostatichyperplasia, prostate cancer, breast cancer, menopausal and andropausalvasomotor conditions, urinary incontinence, sexual dysfunction, erectiledysfunction, depression, uterine fibroid disease, and/or endometriosis,treatment of acne, hirsutism, stimulation of hematopoiesis, malecontraception, impotence, and as anabolic agents, which use includesadministering to a subject an effective amount of a crystalline form ofthe present invention.

In some embodiments, the invention encompasses the use of a crystallineform of the invention in the treatment of muscle injury. In particularembodiments, the muscle injury is a surgery-related muscle injury, atraumatic muscle injury, a work-related skeletal muscle injury, or anovertraining-related muscle injury.

Non-limiting examples of surgery-related muscle injuries include muscledamage due to knee replacement, anterior cruciate ligament (ACL) repair,plastic surgery, hip replacement surgery, joint replacement surgery,tendon repair surgery, surgical repair of rotator cuff disease andinjury, and amputation.

Non-limiting examples of traumatic muscle injuries include battlefieldmuscle injuries, auto accident-related muscle injuries, andsports-related muscle injuries. Traumatic injury to the muscle caninclude lacerations, blunt force contusions, shrapnel wounds, musclepulls or tears, burns, acute strains, chronic strains, weight or forcestress injuries, repetitive stress injuries, avulsion muscle injury, andcompartment syndrome.

In one embodiment, the muscle injury is a traumatic muscle injury andthe treatment method provides for administration of at least one highdose of a crystalline form of the invention immediately after thetraumatic injury (for example, within one day of the injury) followed byperiodic administration of a low dose of a crystalline form of theinvention during the recovery period.

Non-limiting examples of work-related muscle injuries include injuriescaused by highly repetitive motions, forceful motions, awkward postures,prolonged and forceful mechanical coupling between the body and anobject, and vibration.

Overtraining-related muscle injuries include unrepaired orunder-repaired muscle damage coincident with a lack of recovery or lackof an increase of physical work capacity.

In an additional embodiment, the muscle injury is exercise orsports-induced muscle damage resulting including exercise-induceddelayed onset muscle soreness (DOMS).

In another aspect, the invention provides a method of treating a muscledegenerative disorder comprising administering to a human a crystallineform of the invention.

In particular embodiments, the muscle degenerative disorder is musculardystrophy, myotonic dystrophy, polymyositis, or dermatomyositis.

For example, the methods may be used to treat a muscular dystrophydisorder selected from Duchenne MD, Becker MD, Congenital MD (Fukuyama),Emery Dreifuss MD, Limb girdle MD, and Fascioscapulohumeral MD.

The methods of the invention may also be used to treat myotonicdystrophy type I (DM1 or Steinert's), myotonic dystrophy type II (DM2 orproximal myotonic myopathy), or congenital myotonia.

In some embodiments, the invention encompasses a therapeutic combinationin which the crystalline form of the invention is administered in asubject in combination with the implantation of a biologic scaffold(e.g., a scaffold comprising extracellular matrix) that promotes muscleregeneration. Such scaffolds are known in the art. See, for example,Turner and Badylack (2012) Cell Tissue Res. 347(3):759-74 and U.S. Pat.No. 6.576,265. Scaffolds comprising non-crosslinked extracellular matrixmaterial are preferred.

In another aspect, the invention provides a method of treating tendondamage where the method comprises administering a crystalline form ofthe invention to a subject in need thereof. In a particular embodiment,the invention includes a method of enhancing the formation of a stabletendon-bone interface. In a related embodiment, the invention provides amethod of increasing the stress to failure of tendons, for examplesurgically-repaired tendons. In an additional embodiment, the inventionprovides a method of reducing fibrosis at the repair site forsurgically-repaired tendons. In a particular embodiment, the inventionprovides a method of treating tendon damage associated with rotator cuffinjury, or tendon damage associated with surgical repair of rotator cuffinjury. The mammal requiring treatment with a crystalline form of thepresent invention is typically a human being.

In one preferred embodiment, the disorder to be treated is musclewasting associated with chronic obstructive pulmonary disease (COPD).

In another preferred embodiment, the disorder to be treated is musclewasting associated with chronic kidney disease (CKD) or end stage renaldisease (ESRD).

In an alternate preferred embodiment, the disorder to be treated ismuscle wasting associated with chronic heart failure (CHF).

In an additional preferred embodiment, the crystalline form is used toaccelerate bone fracture repair and healing, for example to acceleratethe repair and healing of a hip fracture.

In yet another preferred embodiment, the crystalline form is used totreat urinary incontinence (including urinary incontinence associatedwith muscle and/or tissue wasting of the pelvic floor).

Typically, an effective amount, particularly a therapeutically effectiveamount of the crystalline form is administered according to the methodsof the invention. As used herein, the term “effective amount” means thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system, animal, or human that is beingsought, for instance, by a researcher or clinician. The biological ormedical response may be considered a prophylactic response or atreatment response.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function. For use in therapy,therapeutically effective amounts of a crystalline form may beadministered as the raw chemical. Additionally, the active ingredientmay be presented as a pharmaceutical composition.

Accordingly, the invention further provides pharmaceutical compositionsthat include effective amounts of crystalline forms of the presentinvention and one or more pharmaceutically acceptable carriers,diluents, or excipients. The crystalline forms of the present inventionare as herein described. The carrier(s), diluent(s) or excipient(s) mustbe acceptable, in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipient ofthe pharmaceutical composition.

In accordance with another aspect of the invention there is alsoprovided a process for the preparation of a pharmaceutical formulationincluding admixing a crystalline form of the present invention with oneor more pharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a crystalline form of the presentinvention will depend upon a number of factors. For example, thespecies, age, and weight of the recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration are all factors to be considered. Thetherapeutically effective amount ultimately should be at the discretionof the attendant physician or veterinarian. An effective amount of acrystalline form of the present invention for the treatment of humanssuffering from disorders such as frailty, generally, should be in therange of 0.01 to 100 mg/kg body weight of recipient (mammal) per day.More usually the effective amount should be in the range of 0.001 to 1mg/kg body weight per day. Thus, for a 70 kg adult mammal the actualamount per day would usually be from 0.07 to 70 mg, such as 0.1-20 mg,for example 1-10 mg. This amount may be given in a single dose per dayor in a number (such as two, three, four, five, or more) of sub-dosesper day such that the total daily dose is the same.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.1 mg to 100 mg ofa crystalline form of the present invention, such as 0.1-50 mg, forexample 0.5-15 mg depending on the condition being treated, the route ofadministration, and the age, weight, and condition of the patient.Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient. Such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component may becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the crystalline form to a suitablefine size and mixing with an appropriate pharmaceutical carrier such asan edible carbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents may also bepresent.

Capsules can be made by preparing a powder, liquid, or suspensionmixture and encapsulating with gelatin or some other appropriate shellmaterial. Glidants and lubricants such as colloidal silica, talc,magnesium stearate, calcium stearate, or solid polyethylene glycol maybe added to the mixture before the encapsulation. A disintegrating orsolubilizing agent such as agar-agar, calcium carbonate or sodiumcarbonate may also be added to improve the availability of themedicament when the capsule is ingested. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents, andcoloring agents may also be incorporated into the mixture.

Examples of suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants useful in these dosage forms include, for example, sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum, andthe like.

Tablets can be formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture may be prepared by mixing thecrystalline form, suitably comminuted, with a diluent or base asdescribed above. Optional ingredients include binders such ascarboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone,solution retardants such as paraffin, resorption accelerators such as aquaternary salt, and/or absorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture may be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture may be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules may be lubricated to prevent sticking to thetablet forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The crystalline forms of the present invention may also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material, and a polish coatingof wax may be provided. Dyestuffs may be added to these coatings todistinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs may be prepared indosage unit form so that a given quantity contains a predeterminedamount of the crystalline form. Syrups may be prepared, for example, bydissolving the crystalline form in a suitably flavored aqueous solution,while elixirs are prepared through the use of a non-toxic alcoholicvehicle. Suspensions may be formulated generally by dispersing thecrystalline form in a non-toxic vehicle. Solubilizers and emulsifierssuch as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitolethers may be added. Solubilizers that may be used according to thepresent invention include Cremophor EL, vitamin E, PEG, and Solutol.Preservatives and/or flavor additives such as peppermint oil, or naturalsweeteners, saccharin, or other artificial sweeteners; and the like mayalso be added.

Where appropriate, dosage unit formulations for oral administration maybe microencapsulated. The formulation may also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The crystalline forms of the present invention may also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes may be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

The crystalline forms of the present invention may also be delivered bythe use of monoclonal antibodies as individual carriers to which thecrystalline form molecules are coupled.

The crystalline forms of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers may includepolyvinylpyrrolidone (PVP), pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the crystalline formsmay be coupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from a patch by chemicalenhancers, iontophoresis, noncavitational ultrasound, microneedles,thermal ablation, microdermabrasion, and electroporation as generallydescribed in Nature Biotechnology, 26(11), 1261-1268 (2008),incorporated herein by reference as related to such delivery systems.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring or coloringagents.

The crystalline forms of the present invention may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. For example, in frailty therapy, combinationmay be had with other anabolic or osteoporosis therapeutic agents. Asone example, osteoporosis combination therapies according to the presentinvention would thus comprise the administration of at least onecrystalline form of the present invention and the use of at least oneother osteoporosis therapy such as, for example, Boniva® (ibandronatesodium), Fosamax® (alendronate), Actonel® (risedronate sodium), orProlia™ (denosumab) The crystalline form(s) of the present invention andthe other pharmaceutically active agent(s) may be administered togetheror separately and, when administered separately, administration mayoccur simultaneously or sequentially, in any order. The amounts of thecrystalline form(s) of the present invention and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. The administration in combination of a crystallineform of the present invention with other treatment agents may be incombination by administration concomitantly in: (1) a unitarypharmaceutical composition including both crystalline forms; or (2)separate pharmaceutical compositions each including one of thecrystalline forms. Alternatively, the combination may be administeredseparately in a sequential manner wherein one treatment agent isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

Other potential therapeutic combinations include the crystalline formsof the present invention combined with other crystalline forms of thepresent invention, growth promoting agents, growth hormone secretagogues(e.g., ghrelin), growth hormone releasing factor and its analogs, humangrowth hormone and its analogs (e.g., Genotropin®, Humatrope®,Norditropin®, Nutropin®, Saizen®, Serostim®), somatomedins,alpha-adrenergic agonists, serotonin 5-HT_(D) agonists, agents thatinhibit somatostatin or its release, 5-α-reductase inhibitors, aromataseinhibitors, GnRH agonists or antagonists, parathyroid hormone, estrogen,testosterone, SERMs, progesterone receptor agonists or antagonists,and/or with other modulators of nuclear hormone receptors.

The crystalline forms of the present invention may be used in thetreatment of a variety of disorders and conditions and, as such, thecrystalline forms of the present invention may be used in combinationwith a variety of other suitable therapeutic agents useful in thetreatment of those disorders or conditions. Non-limiting examplesinclude combinations of the present invention with anti-diabetic agents,anti-osteoporosis agents, anti-obesity agents, anti-inflammatory agents,anti-anxiety agents, anti-depressants, anti-hypertensive agents,anti-platelet agents, anti-thrombotic and thrombolytic agents, cardiacglycosides, cholesterol or lipid lowering agents, mineralocorticoidreceptor antagonists, phosphodiesterase inhibitors, kinase inhibitors,thyroid mimetics, anabolic agents, viral therapies, cognitive disordertherapies, sleeping disorder therapies, sexual dysfunction therapies,contraceptives, cytotoxic agents, radiation therapy, anti-proliferativeagents, and anti-tumor agents. Additionally, the crystalline forms ofthe present invention may be combined with nutritional supplements suchas amino acids, triglycerides, vitamins (including vitamin D; see, forexample Hedström et al. (2002) J Bone Joint Surg Br. 84(4):497-503),minerals, creatine, piloic acid, carnitine, or coenzyme Q10.

In particular, the crystalline forms of the present invention arebelieved useful, either alone or in combination with other agents in theacceleration of wound healing and the treatment of hypogonadism,sarcopenia, osteoporosis, muscle wasting, wasting diseases, cachexia(including cachexias associated with cancer, chronic obstructivepulmonary disease (COPD), end stage renal disease (ESRD), heart failure,HIV illness, HIV treatment, and diabetes mellitus type 1 and type 2),frailty, dry eye, prostatic hyperplasia, prostate cancer, breast cancer,menopausal and andropausal vasomotor conditions, urinary incontinence,sexual dysfunction, erectile dysfunction, depression, uterine fibroiddisease, endometriosis, acne, hirsutism, male contraception, impotence,and in the use as male and female hormone replacement therapy, as astimulant of hematopoiesis, and as an anabolic agent.

Abbreviations

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, thefollowing abbreviations may be used in the examples and throughout thespecification:

g (grams); mg (milligrams); L (liters); mL (milliliters); μL(microliters); N (normal); M (molar); mM (millimolar); Hz (Hertz); MHz(megahertz); mol (moles); mmol (millimoles); rt (room temperature); min(minute); h (hour); d (day); MS (mass spec); LCMS (liquid chromatographymass spec); GCMS (gas chromatography mass spec; ESI (electrosprayionization); HPLC (high performance liquid chromatography); psi (poundsper square inch); H₂ (hydrogen gas) Pd(C) palladium on carbon; ee(enantiomeric excess); NH₄Cl (ammonium chloride); THF (tetrahydrofuran);MeCN (acetonitrile); CH₂Cl₂ (methylene chloride); Pd(PPh₃)₄ (palladiumtetrakistriphenyl phosphine); NaOH (sodium hydroxide); TFA(trifluoroacetic acid); CDCl₃ (deuterated chloroform); CD₃OD (deuteratedmethanol); SiO₂ (silica); DMSO (dimethylsulfoxide); EtOAc (ethylacetate); Na₂SO₄ (sodium sulfate); HCl (hydrochloric acid); CHCl₃(chloroform); DMF (N,N-dimethylformamide); PhMe (toluene); Cs₂CO₃(cesium carbonate); Me (methyl); Et (ethyl); EtOH (ethanol); MeOH(methanol); t-Bu (tert-butyl); Et₂O (diethyl ether); N₂ (nitrogen);sat'd (saturated); NaHCO₃ (sodium bicarbonate); K₂CO₃ (potassiumcarbonate); Zn(CN)₂ (zinc cyanide); NMP (N-methyl-2-pyrrolidone); DIEA(diisopropylethyl amine); LiBH₄ (lithium borohydride); Et₃N(triethylamine); Oxone (potassium peroxomonosulfate); LDA (lithiumdiisopropylamide); Na₂S₂O₃ (sodium thiosulphate); DIPA(diisopropylamine); PTFE (polytetrafluoroethylene); KOtBu (potassiumt-butoxide); hex (hexanes); semiprep (semipreparative); NaCNBH₃ (sodiumcyanoborohydride); CuI (copper iodode); Pd(PPh₃)₂Cl₂(bis(triphenylphosphine)palladiumchloride); anhyd (anhydrous); DMAC(dimethyacetamide); dppf (1,1′-bis(diphenylphosphino)ferrocene);Pd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(0); PMHS(polymethylhydrosiloxane); MsCl (mesyl chloride); Aq (aqueous); TBAF(tetra-n-butylammonium fluoride) n-BuLi (n-butyllithium); TsOH (tosicacid); MTBE (methyl t-butyl ether); Boc₂O (di-t-butyl dicarbonate).

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions conducted under an inert atmosphereat room temperature unless otherwise noted. Reagents employed withoutsynthetic details are commercially available or made according toliterature procedures.

X-ray powder diffraction (XRPD) data as shown in FIGS. 1 and 2 wereacquired on a PANalytical X'Pert Pro powder diffractometer, modelPW3040Pro, using an X'Celerator detector. The acquisition conditions were:radiation: Cu Kα, generator tension: 45 kV, generator current: 40 mA;step size: 0.0084° 2θ; continuous scan; incident beam optics: mirroroptics—Cu W/Si (Focusing MPD), ½ degree fixed divergence slit, 0.02radian soller slits; diffracted beam optics: programmable anti-scatterslit assembly (X'celerator module) set to fixed ½ degree anti-scatterslit, 0.02 radian soller slits, measurement temperature: 20-25° C. Thesample was prepared by packing sample in a 1.0 mm capillary. Peakpositions were obtained using PANalytical X'Pert Highscore Plussoftware. The margin of error is approximately ±0.1° 2θ for each of thepeak assignments.

¹³C and ¹⁹F solid state NMR data as shown in FIGS. 3-6 were acquiredusing a Bruker Avance 500 triple-resonance spectrometer operating at a¹H frequency of 499.98 MHz. The ¹³C SSNMR spectra shown were obtainedusing a cross-polarization pulse sequence with a Bruker 4-mm tripleresonance magic-angle spinning probe at a rotor frequency of 8 kHz. Alinear power ramp from 75 to 90 kHz was used on the ¹H channel toenhance cross-polarization efficiency. Spinning sidebands wereeliminated by a five-pulse total sideband suppression pulse sequence. ¹Hdecoupling was obtained using the Spinal-64 sequence. The ¹⁹F SSNMRspectra shown were obtained using a cross-polarization pulse sequencewith a Bruker 4-mm triple resonance magic-angle probe at a rotorfrequency of 12.5 kHz. The sample temperature was approximately 0° C.Characteristic ¹³C and ¹⁹F NMR peak positions are reported relative totetramethylsilane at 0 ppm (parts per million) and are quoted to aprecision of +/−0.2 ppm, because of instrumental variability andcalibration.

EXAMPLES Example 1 Synthesis of(R)-1-(1-(methylsulfonynpropan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

Method 1:

A. (R)-1-(Methylthio)propan-2-amine

Step 1

To a solution of commercially available (R)-2-aminopropan-1-ol (5 g,66.6 mmol) in MeCN (20 mL), in an ice bath, is added very slowly,dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic).The reaction mixture is kept in the cold bath for ˜10 min, and then atrt for ˜30 min. After stirring for another ˜10 minutes, the solids arecollected by filtration, washed sequentially with MeCN (40 mL) andhexanes (100 mL), and dried by air suction for ˜40 min. to produce theintermediate ((R)-2-aminopropyl hydrogen sulfate.

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL)is added solid NaOH (2.66 g, 66.6 mmol) in portions over ˜10 min. Thenthe intermediate from step 1 is added as a solid over ˜5 min. Themixture is then heated at 90° C. for ˜10 h. The reaction mixture isbiphasic. Upon cooling, MTBE (20 mL) is added, and the organic phase(brownish color) is separated. The aqueous phase is extracted with MTBE(2×20 mL). The original organic phase is washed with 1N NaOH (15 mL).The basic aqueous phase is re-extracted with MTBE (2×20 mL). All theether phases are combined, dried over Na₂SO₄, filtered, and concentrated(carefully, since the product is volatile) to afford the crude productas a light yellow oil.

Method 2

(R)-1-(methylthio)propan-2-amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1-ol (135 g, 1797 mmol) isdissolved in MeOH 1350 mL). The solution is cooled to 5° C. with anicebath, then Boc₂O (392 g, 1797 mmol) is added as a solution in MeOH(1000 mL). The reaction temperature is kept below 10° C. After theaddition, the cooling bath is removed, and the mixture is stirred for 3h. The MeOH is removed under vacuum (rotavap bath: 50° C.). Thismaterial is used as is for the next step.

Step 2

The residue is dissolved in CH₂Cl₂ (1200 mL) and NEt₃ (378 mL, 2717mmol) is added, then the mixture is cooled on an ice bath. Next, MsCl(166.5 mL, 2152 mmol) is added over ˜2 h, while keeping the reactiontemperature below 15° C. The mixture is stirred in an icebath for 1 hthen the bath was removed. The mixture is stirred for 3 d, then washedwith a 10% NaOH solution (500 mL 3×), then with water. The organic phaseis dried with MgSO₄, filtered, then stripped off (rota, 50° C.waterbath. The impure residue is dissolved in a mix of 500 mL EtOAc (500mL) and MTBE (500 mL) and then extracted with water to remove allwater-soluble salts. The organic phase is dried with MgSO₄, filtered,then stripped off to afford a white solid residue.

B. (R)-tert-Butyl (1-(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) is stirred with DMF (200 mL) to afford asuspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propylmethanesulfonate (97 g, 383 mmol) is added portionwise while thetemperature is kept below 45° C. (exothermic). After the addition, themixture is stirred for 2 h, then toluene (100 mL) is added. The mixtureis washed with water (500 mL, 4×), then dried with MgSO₄, and filtered.The filtrate is stripped off (rotavap) to a pale yellow oil.

C. (R)-1-(Methylthio)propan-2-amine hydrochloride

Acetyl chloride (150 mL,) is added to a stirred solution of MeOH (600mL) cooled with an icebath. The mixture is stirred for 30 min in anicebath, then added to (R)-tert-butyl(1-(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture isstirred at rt for 2 h, (CO₂, (CH₃)₂C═CH₂ evolution) and then strippedoff to a white solid.

D. 4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile

To a freshly prepared solution of LDA (119 mmol) in anhyd THF (250 mL)at −45° C. is added a solution of commercially available4-fluoro-2-(trifluoromethyl)benzonitrile (21.5 g, 114 mmol) in THF (30mL), dropwise at a rate such that the internal temperature remained<−40° C. (became dark brown during addition). The mixture is stirred 30min at −45° C., cooled to −70° C. and iodine (31.7 g, 125 mmol) is addedin one portion (−70° C.→−52° C.). The mixture is stirred for 1 h,removed from the cooling bath and quenched by addition of 10% Na₂S₂O₃(ca. 250 mL) and 1N HCI (ca. 125 mL). The mixture is extracted withEtOAc (×3). Combined organics are washed (water, brine), dried overNa₂SO₄ and concentrated in vacuo. The residue is purified by lowpressure liquid chromatography (silica gel, EtOAc/hexanes, gradientelution) followed by recrystallization from heptane (30 mL), twice,affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1mmol, 44.1% yield) as a pale yellow solid.

E. 4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile

A 20 mL vial is charged with4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile, (0.315 g, 1.00 mmol),Pd(PPh₃)₂Cl₂ (0.014 g, 0.020 mmol) and CuI (0.0076 g, 0.040 mmol), andsealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1.500mmol) are added via syringe and the mixture is degassed 10 min bysparging with N2 while immersed in an ultrasonic bath.Ethynyltrimethylsilane (0.155 mL, 1.100 mmol) is added dropwise viasyringe and the septum is replaced by a PTFE-faced crimp top. Themixture is stirred in a heating block at 60° C. Upon cooling the mixtureis diluted with EtOAc and filtered through Celite. The filtrate iswashed (satd NH₄Cl, water, brine), dried over Na₂SO₄ and concentrated invacuo. The residue is purified by low pressure liquid chromatography(silica gel, EtOAc/hexanes, gradient elution) affording4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile.

F.(R)-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

A mixture of4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile(1.16 g, 4.07 mmol), (R)-1-(methylthio)propan-2-amine (0.599 g, 5.69mmol) and DIEA (1.42 mL, 8.13 mmol) in DMSO (7 mL) is heated (sealedtube) at 100° C. for 50 min. Upon cooling, the reaction mixture isdiluted with EtOAc (50 mL) and washed with water (30 mL). The organicphase is washed with water and brine, dried over Na₂SO₄, filtered andconcentrated to give the intermediate aniline. This intermediate isdissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60mmol) and heated at 50° C. The reaction is monitored by LCMS, and deemedcomplete after 40 min. Upon cooling, the reaction mixture is dilutedwith EtOAc (40 mL) and washed with water (30 mL). The organic phase iswashed with more water and brine, dried over Na₂SO₄, filtered andconcentrated. The residue is chromatographed over silica gel using a5-40% EtOAc-hexane gradient to give the thioether intermediate:

G.(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

To an ice-cold solution of(R)-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile(0.560 g, 1.88 mmol) in MeOH (10 mL) is added a solution of Oxone (4.04g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture isdiluted with water (30 mL) and extracted with EtOAc (50 mL). The organicphase is washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue is chromatographed over silica gel using 100%CH₂Cl₂ to give(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrileas a white foam that is crystallized from CH₂Cl₂/hexanes to afford awhite solid.

Example 2 Preparation of Crystalline Form 1 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile(1.74 kg, 1 wt) was dissolved in ethyl acetate (12.0 Kg, 6.9 wt) at20-30° C. The solution was transferred into a clean reaction vessel viaan in-line cartridge filter. The solution was concentrated to ˜3.0-5.0volumes under reduced pressure, keeping the temperature below 50° C. Thesolution was cooled to 20-30° C., and n-heptane (23.0 Kg, 13.2 wt) wasadded slowly over ˜1 hour. The solution was stirred 1-2 hrs at 20-30°C., heated to 50-55° C. for 2-3 hours, cooled back to 20-30° C. andstirred for 1-2 hours. The slurry was sampled and analyzed by XRPD. Thesolid was collected by filtration, washed with n-heptane (1.4 Kg, 0.8wt), and dried in vacuo at 40-50° C. to provide crystalline(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile(1.54 Kg, Form 1; 88.5% yield, 99.5% purity) as a slightly coloredsolid.

Example 3 Preparation of Crystalline Form 2 of(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

Crude(R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile(1.54 g [theoretical], 1 wt) was dissolved in dichloromethane (5 mL,3.25 vol) and loaded onto a 12-g ISCO column (SiO2). The column waseluted with DCM (˜500 mL, 325 vol) and the product-containing fractionswere combined and concentrated in vacuo. The resulting residue wastriturated in n-heptane. The solid was collected by filtration,air-dried, and placed under high vacuum for 3 h to provide GSK2881078A(1.009 g, Form 2; 65.1% yield, 100% AUC HPLC-UV) as a white solid.

That which is claimed:
 1. A crystalline form of:

that is characterized by an X-ray powder diffraction (XRPD) pattern thathas the representative peaks: Position [° 2Theta] d-spacing [A]  9.2 ±0.1 9.6 11.4 ± 0.1 7.8 11.9 ± 0.1 7.4 13.8 ± 0.1 6.4 15.4 ± 0.1 5.7 17.8± 0.1 5.0 18.0 ± 0.1 4.9 18.5 ± 0.1 4.8 18.7 ± 0.1 4.7 23.2 ± 0.1  3.8.


2. The crystalline form of claim 1 that is further characterized by anXRPD pattern substantially in accordance with FIG.
 1. 3. The crystallineform of claim 1 that is further characterized by an ¹⁹F SSNMR spectrumcomprising isotropic chemical shifts at −52.7±0.2, 56.0±0.2 and−57.1±0.2 ppm, wherein the ¹⁹F SSNMR spectrum is obtained on aspectrometer operating at a frequency of 470.40 MHz for ¹⁹F observationusing a cross-polarization pulse sequence with a Bruker 4-mm tripleresonance magic-angle spinning probe at a rotor frequency of 12.5 kHz.4. The crystalline form of claim 1 that is further characterized by an¹⁹F SSNMR spectrum substantially in accordance with FIG.
 4. 5. Thecrystalline form of claim 1 that is further characterized by an ¹³CSSNMR (solid state nuclear magnetic resonance) spectrum comprisingisotropic chemical shifts at 140.1±0.2, 136.9±0.2, 134.9±0.2, 130.4±0.2,128.5±0.2, 126.6±0.2, 126.0±0.2, 125.7±0.2, 124.8±0.2, 121.9±0.2,120.9±0.2, 119.7±0.2, 118.6±0.2, 115.5±0.2, 115.1±0.2, 103.6±0.2,100.3±0.2, 98.9±0.2, 58.1±0.2, 55.7±0.2, 54.7±0.2, 51.1±0.2, 50.4±0.2,44.7±0.2, 43.6±0.2, 40.7±0.2, 23.5±0.2 and 20.7±0.2 ppm, wherein the ¹³CSSNMR spectrum is obtained on a spectrometer operating at a frequency of125.73 MHz for ¹³C observation using a cross-polarization pulse sequencewith a Bruker 4-mm triple resonance magic-angle spinning probe at arotor frequency of 8 kHz.
 6. The crystalline form of claim 1 that isfurther characterized by an ¹³C SSNMR spectrum substantially inaccordance with FIG.
 3. 7. The crystalline form of claim 1 when preparedby crystallization from a solvent system that is ethyl acetate andn-heptane.
 8. The crystalline form of claim 1 when prepared bycrystallization from a solvent system that is other than dichloromethaneand hexanes.
 9. A method of treating a disorder selected from musclewasting associated with chronic obstructive pulmonary disease (COPD),muscle wasting associated with chronic kidney disease (CKD), musclewasting associated with chronic heart failure (CHF), and urinaryincontinence, wherein said method comprises administering a compoundaccording to claim 1 to a human subject.
 10. A method of acceleratinghip fracture repair and healing wherein said method comprisesadministering a compound according to claim 1 to a human subject.
 11. Aprocess for preparing a crystalline form of:

that is characterized by an X-ray powder diffraction (XRPD) pattern thathas the representative peaks: Position [° 2Theta] d-spacing [A]  9.2 ±0.1 9.6 11.4 ± 0.1 7.8 11.9 ± 0.1 7.4 13.8 ± 0.1 6.4 15.4 ± 0.1 5.7 17.8± 0.1 5.0 18.0 ± 0.1 4.9 18.5 ± 0.1 4.8 18.7 ± 0.1 4.7 23.2 ± 0.1 3.8

which process comprises crystallization from a solvent system that isethyl acetate and n-heptane.
 12. A process for preparing a crystallineform of:

that is characterized by an X-ray powder diffraction (XRPD) pattern thathas the representative peaks: Position [° 2Theta] d-spacing [A]  9.2 ±0.1 9.6 11.4 ± 0.1 7.8 11.9 ± 0.1 7.4 13.8 ± 0.1 6.4 15.4 ± 0.1 5.7 17.8± 0.1 5.0 18.0 ± 0.1 4.9 18.5 ± 0.1 4.8 18.7 ± 0.1 4.7 23.2 ± 0.1 3.8

which process comprises crystallization from a solvent system that isother than dichloromethane and hexanes.